Integrated stress response associated with dark microglia contributes to neurodegeneration [TRAP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1098742 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28618403.fastq.gz | Fastqsanger.gz | |||
| SRR28618404.fastq.gz | Fastqsanger.gz | |||
| SRR28618405.fastq.gz | Fastqsanger.gz | |||
| SRR28618406.fastq.gz | Fastqsanger.gz | |||
| SRR28618407.fastq.gz | Fastqsanger.gz |
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Project description:Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a microglia phenotype characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct “dark” microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long- chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.
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Project description:<p>Microglia, the brain’s primary resident immune cells, can assume various phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer’s disease (AD), where microglia are a leading causal cell type, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a subset of microglia with neurodegenerative outcomes. ISR is activated in AD-associated microglia subsets, including the ultrastructurally distinct “dark” microglia linked to pathological synapse loss. Activation of ISR in microglia is sufficient to induce early features of dark microglia. In AD models, microglial ISR exacerbates neurodegenerative pathologies, such as Tau and synapse loss, while inhibiting microglial ISR ameliorates them. Mechanistically, we present evidence that ISR in microglia promotes the secretion of toxic long-chain lipids that impair neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR and lipid synthesis ameliorates synapse loss in AD models. Our results demonstrate that activation of ISR within microglia represents a pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of toxic long-chain lipids from ISR-activated microglia. </p>
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